We are analyzing the interactions between virus glycoproteins and their receptors for several enveloped viruses important for human health. Our goals are to define mechanisms of virus fusion and entry, elucidate mechanisms of virus tropism, identify cellular receptors, develop strategies to elicit and detect neutralizing antibodies, and develop novel therapeutic and preventative approaches. 1) Human herpesvirus 6 (HHV-6) is the etiologic agent of exanthema subitum and causes opportunistic infections in immunocompromised patients; it has also been implicated in multiple sclerosis and in the progression of AIDS. We discovered that the two major HHV-6 subgroups (A and B) use human CD46 as a cellular receptor. This was demonstrated by the specific downregulation of surface CD46 during HHV-6 infection, the inhibitory activities of anti-CD46 antibodies on HHV-6 infection and cell fusion, and by the ability of recombinant CD46 to render nonhuman cells susceptible to HHV-6 infection and fusion. CD46, also used as a receptor by measles virus, is an important regulator of complement activation. The use of a ubiquitous immunoregulatory receptor opens novel perspectives for understanding the tropism and pathogenicity of HHV-6. 2) Hepatitis C virus is a major human pathogen associated with chronic liver disease and hepatocellular carcinoma. Research on this virus is severely hampered by the absence of a suitable cell culture system in which to propagate the virus and study its life cycle. We seek to apply our cell fusion assay systems to study the function of HCV viral glycoproteins (E1 and E2). The goals are to develop systems to analyze activity of these glycoproteins, test the activities of neutralizing antibodies, and identify the cellular receptor(s). To this end, we have shown that E1/E2 can mediate low pH-induced fusion with human hepatocyte cell lines. We are optimizing this system for analysis of neutralizing antibodies, and for screening cDNA libraries for the cellular receptor(s).